Calcium antagonists of the dihydropyridine type and their uses, for example as cardiovascular agents, are known (see British Patent 1 173 862; British Patent 1 358 951; U.S. Pat. No. 4,256,749; DE-OS 33 11 003). Those compounds, such as nifedipine, which is one of the most well known representatives of the group, are used especially for the treatment of coronary heart disease, for the prophylaxis of attacks of Angina pectoris and for the treatment of hypertension.
Various dosage forms are known which, depending upon the galenical characteristics, are suitable in various forms for the treatment of the above indications. Attention should be paid especially also to the physico-chemical properties of the substance. Nifedipine and other calcium antagonists of the dihydropyridine type are only very slightly soluble in water. For example, a maximum of 10 mg of nifedipine is soluble in 1000 ml of simulated gastric or intestinal fluid (0.001%). Solubilities of less than 0.3% in aqueous media are likely to give rise to absorption problems which manifest themselves in a reduction in the rate of absorption and in the amount absorbed (Barker et al.; Austral. J. Pharm. 49, 33-43, 1968).
For example, crystalline nifedipine is absorbed so slowly that the pharmacokinetic elimination rate exceeds the absorption rate. In comparison with capsules containing nifedipine in dissolved form, this results in plasma levels that are relatively low but fall more slowly (so-called Flip-Flop; Wagner JG., Fundamentals of Clinical Pharmacokinetics, Hamilton, III. 1975, Drug Intelligence Publications). For example, according to G. Pabst et al., Arzneim.-Forsch./Drug Res. 36(1), 256-260, 1986, after the administration of 20 mg of dissolved nifedipine in capsules, plasma level peaks of about 200 ng/ml are found as early as after about 30 minutes. After the administration of the same dose of crystalline nifedipine, the plasma level peaks after about 1.5 hours are about 40 ng/ml. Nifedipine dissolved in capsules therefore achieves plasma levels that are high but fall rapidly, whereas the administration of the same dose in crystalline form in tablets results in plasma levels that are lower but longer lasting.
Nifedipine in capsules is used especially when an immediate effect is required (treatment of an attack of Angina pectoris, treatment of hypertensive crises). The dosage is then 3.times.5 mg, 3.times.10 mg or 3.times.20 mg daily. However, the rapid rate of nifedipine influx increases the risk regarding reflex tachycardia.
In order to attain and maintain constant levels of active ingredients in the plasma there are used, on the one hand, infusion solutions, which are, however, unsuitable for ambulant treatment, or, on the other hand, retard preparations from which the active ingredient is released only in a delayed manner into the biological system.
Nifedipine in crystalline form is therefore especially suitable, for example, for long-term ambulant treatment of hypertension or coronary heart disease. The most customary dosage is 2.times.20 mg daily. In many cases the dosage has to be increased to 2-3.times.40 mg per day. The solubility behaviour and thus also the absorption rate can be controlled to a certain degree via the crystal size of nifedipine (EP 47 899).
For the manufacture of retard preparations it is also possible to use amorphous nifedipine by controlling the superior solubility of the non-crystalline form in comparison to the crystalline form, by using suitable excipients (EP 232 155; EP 220 760; DE-OS 30 24 858). Several possible methods of manufacturing amorphous nifedipine preparations having improved solubility behaviour on the basis of the molecularly disperse presence of the substance have been disclosed (cf. DE-OS 28 22 882). The preparation of amorphous nifedipine generally requires organic solvents, there being used especially methylene chloride because of its excellent dissolving power. Where possible, however, chlorinated hydrocarbons should be avoided in the manufacture of modern medicaments. Ethanol is a less efficient solvent, since nifedipine is much less soluble therein and therefore large amounts of solvent are required. In addition, in the amorphous state the material is generally unstable and may change into the more stable crystalline form again, for which triggering factors include heat and moisture.
Known pharmaceutical preparations having delayed release of nifedipine, for example AdalatR retard or CorotrendR retard, involve especially twice daily administration and, as in vitro tests show, release 60-90% of the total dose of the medicinal substance within 8 hours (see Table 1). The lowest plasma levels regarded as still being effective, approximately 10-15 ng/ml, are attained as early as 6 to 8 hours after the administration of 20 mg (see Pabst and EP 220 760). When a tablet containing 40 mg of nifedipine is used, the plasma levels after 12 hours fluctuate above the necessary minimum effective concentration (EP 220 760), but the 40 mg form described rapidly attains plasma level peaks of more than 60 ng/ml initially which then, in accordance with the specific elimination kinetics (Flip-Flop model), fall to about 20-25 ng/ml within the first 9 hours. After 16 hours the concentrations are about 15-17 ng/ml and after 24 hours they are still about 8-11.4 ng/ml. That plasma level behaviour is not optimum for once-daily administration, since in order to obtain plasma levels above the minimum effective threshold during the second twelve hours it is necessary to accept high plasma levels during the first 12 hours. As mentioned above, the rapid influx rate of nifedipine in conjunction with high plasma level peaks has repeatedly been associated with an increased side-effect rate (tachycardia) and reduced effectiveness in lowering blood pressure (Kleinbloessem et al.; Clin. Pharmacol. Ther. 35,6, 742-749, 1984).
Accordingly, it would be desirable to have nifedipine formulations that are distinguished by a slow influx rate and small plasma level fluctuations, that is to say plasma levels that remain constant over a relatively long period. That medicament should provide, as early as on the first administration or on repeated administration, constant, therapeutically effective plasma levels exhibiting a minimum of fluctuations between the maximum and minimum concentrations of active ingredient in the blood. A possible method of reducing the influx time of the active ingredient and of minimising fluctuations lies in controlling the dissolution of the active ingredient over an even longer period of time than is the case with conventional retard formulations. That requires the active ingredient to be absorbed over the entire gastrointestinal tract.
A solution to this problem is offered by the therapeutic system OROS.sup.R (F. Theeuwes, J. Pharm. Sci., Vol. 64,12, 1987-1991, 1975) which has already been described for sparingly soluble active ingredients with a double chamber system (U.S. Pat. No. 4,111,202) and especially for nifedipine (BE 898 819). It can be seen from Table 1 that the system containing 30 mg of nifedipine releases only about 20% of the total dose after the first 8 hours. The liberation rate from the third hour is linear, that is to say about 3.33-4% (i.e. 0.9-1.2 mg) of the total dose are released per hour. That release principle differs quite clearly from the dissolution curves of conventional retard forms for twice-daily administration in which after 8 hours 60-100% of the dose, generally 20 mg, are released with a non-linear profile (Table 1). Using the OROS therapeutic system it is possible with 30 mg of nifedipine to maintain plasma levels of approximately 10-20 ng/ml over a period of 24 hours without the necessity to accept plasma level peaks. A disadvantage of the OROS systems is that they are technically difficult to produce.
The release rate from tablets or powders is influenced by the solubility characteristics of the active ingredient which, in turn, depend upon particle size, specific surface area and interactions with excipients. Dissolution can be retarded by means of diffusion barriers in the core of the tablet or in a film coating. Retarding dissolution by means of diffusion barriers in the core is a principle that is frequently used on account of its technical simplicity. It is possible to use various excipients, for example swelling agents, lipophilic substances or alternatively plastics, as diffusion barriers. The matrix, that is to say the homogeneous substance composition, can be such that the release of the active ingredient takes place by diffusion of the dissolved active ingredient especially through the water-filled pores in the tablet core and if required in special cases by diffusion through the retarding substance which must for that purpose be in a suitable structural form. Alternatively the matrix also can be in a form that is subjected to slow erosion and in this way effects delayed release of the active ingredient.
In all those cases the diffusion path and the active diffusion surface for the release change with time. For that reason it is clear that with matrix systems neither in vivo nor in vitro is it usually possible to expect any release having linear kinetics, that is to say of the 0.sup.th order. Instead, the release is generally a function of the root of the time (Square root dissolution; Higuchi; J. Pharm. Sci. 52,12,1963, 1145). The validity of the Higuchi law for the hydrocolloid matrix has also been documented in numerous publications (Ford et al., Int. J. Pharm., 24, 1985, 327-338; 339-350; 1985).
Therapeutic dosage forms in which the medicinal substance is incorporated into a soluble or erodible matrix would be desirable per se on account of the ease of their manufacture, the low degree of variation between different manufacturing processes and because of the relatively low costs.
The use of hydrophilic gums, such as hydroxypropylmethylcellulose, as delaying matrix material is known and has been tested with a large number of active ingredients, but no formulation has been disclosed hitherto that would be suitable for attaining the desired objectives with calcium antagonists of the dihydropyridine type, such as nifedipine.
The behaviour of a specific medicinal substance when combined with a retarding excipient cannot be calculated or generally predicted. Although the basic factors affecting release from matrix systems have been well researched, interactions between the retarding material on the one hand and the active ingredient and other excipients on the other can affect the retarding action in various ways.
In particular, the manufacture of monolithic matrix forms having a release profile according to the 0.sup.th order is one of the important problems of galenical pharmacy. Long-term release systems that obey the Higuchi law of release are disadvantageous because the release rates decline markedly with time.
A release rate of the 0.sup.th order is difficult to produce because, as mentioned, for geometric reasons lengths of diffusion path for the active ingredient that are dependent upon time and rate of release have to be overcome. The release rate decreases as the length of the diffusion path increases, that is to say as time passes less and less substance is released.
It is therefore remarkable that in certain cases and under favourable conditions both readily soluble and sparingly soluble medicinal substances exhibit a linear dissolution principle from matrix systems containing hydroxypropylmethylcellulose (HPMC) (Ranga Rao et al., Drug Development and Industrial Pharmacy, 14 (15-17), 2299-2320, 1988 and Ranga Rao et al., J. of Controlled Release, 12, 1990, 133-141). The solubility of the medicinal substance is therefore not absolutely critical for release of the 0.sup.th order.
The question of release kinetics is a multi-factored problem in which, in addition to the dissolution properties of the active ingredient, a part is played by the rate of water absorption and thus the rate of swelling of the interface to be penetrated, the diffusion coefficient of the substance through the swollen mass and also the time-dependent thickness thereof. It can clearly be imagined that release of the 0.sup.th order is brought about by the existence of an equilibrium between the erosion of the tablet and the dissolution of the active ingredient, so that the diffusion paths for the substance remain constant over the dissolution time. Such a pharmaceutical dosage form cannot be prepared without inventive activity.
Published data of S. Leucuta et al. (Pharmazie, 43, 1988, 845 ff) show, in addition, that the Higuchi release kinetics are observed in the case of a nifedipine/HPMC system under customary conditions.